Avapritinib in Patients With Advanced Gastrointestinal Stromal Tumors Following at Least Three Prior Lines of Therapy

George, Suzanne; Jones, Robin L.; Bauer, Sebastian; Kang, Yoon Koo; Schöffski, Patrick; Eskens, Ferry A.L.M.; Mir, Olivier; Cassier, P.; Serrano, César; Tap, William D.; Trent, Jonathan C.; Rutkowski, Piotr; Patel, Shreyaskumar; Chawla, Sant P.; Meiri, E.; Gordon, Michael; Zhou, Teresa; Roche, Maria; Heinrich, Michael C.; Mehren, Margaret von

doi:10.1002/onco.13674

Cited by 35 publications

(22 citation statements)

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“…Cytopenias were the most common ≥grade 3 AEs, and they occurred at a higher rate in patients who had baseline cytopenias. Cognitive events and ICB have previously been reported in patients with GIST treated with avapritinib 27 . Although symptoms such as brain fog and memory impairment are known disease features of SM 35 , cognitive effect AEs were less frequent in this AdvSM population than those previously observed in patients with GIST 27 , which may be related to the lower starting doses in this study.…”

Section: Discussionmentioning

confidence: 81%

“…The US Food and Drug Administration (FDA) approved avapritinib in June 2021 for adult patients with AdvSM, including patients with ASM, SM-AHN and MCL. It was also recently approved in the United States for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring platelet-derived growth factor receptor alpha ( PDGFRA ) exon 18 mutations at a recommended starting dose of 300 mg once daily (QD), based on dose-escalation and dose-expansion trials that evaluated efficacy and safety in this setting 27 , 28 . We describe the results of a phase 1 international, multicenter, open-label study (EXPLORER, NCT02561988 ) evaluating the safety, pharmacokinetics (PK), efficacy and patient-reported outcomes (PROs) of avapritinib in adult patients with AdvSM and other myeloid malignancies.…”

Section: Mainmentioning

confidence: 99%

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Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial

DeAngelo

Radia

George

et al. 2021

Nat Med

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Advanced systemic mastocytosis (AdvSM) is a rare hematologic neoplasm driven by the KIT D816V mutation and associated with poor survival. This phase 1 study (NCT02561988) evaluated avapritinib (BLU-285), a selective KIT D816V inhibitor, in patients with AdvSM. The primary endpoints were the maximum tolerated dose, recommended phase 2 dose and safety of avapritinib. Secondary endpoints included overall response rate and changes in measures of mast cell burden. Avapritinib was evaluated at doses of 30–400 mg once daily in 86 patients, 69 with centrally confirmed AdvSM. Maximum tolerated dose was not reached, and 200 mg and 300 mg daily were studied in dose-expansion cohorts. The most frequent adverse events observed were periorbital edema (69%), anemia (55%), diarrhea (45%), thrombocytopenia (44%) and nausea (44%). Intracranial bleeding occurred in 13% overall, but in only 1% of patients without severe thrombocytopenia (platelets <50 × 109/l). In 53 response-evaluable patients, the overall response rate was 75%. The complete remission rate was 36%. Avapritinib elicited ≥50% reductions in marrow mast cells and serum tryptase in 92% and 99% of patients, respectively. Avapritinib induced deep and durable responses, including molecular remission of KIT D816V in patients with AdvSM, and was well tolerated at the recommended phase 2 dose of 200 mg daily.

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Section: Discussionmentioning

confidence: 81%

Section: Mainmentioning

confidence: 99%

Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial

DeAngelo

Radia

George

et al. 2021

Nat Med

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“…Reported treatment options for patients with advanced GIST, independent of the tumor genotype, after the failure of approved TKI therapies include avapritinib, cabozantinib, pazopanib, and imatinib rechallenge [4]. In a recently published analysis of the phase I NAVIGATOR trial, avapritinib as at least fourth-line therapy for advanced GISTs with KIT or non-D842V PDGFRA mutations showed a mPFS of 3.7 months, objective response rate (ORR) of 17%, and mOS of 11.6 months [12]. Also, cabozantinib as third-line therapy showed a mPFS of 5.5 months, ORR of 14%, and mOS of 18.2 months in a single-arm phase II study [13].…”

Section: Discussionmentioning

confidence: 99%

Clinical Benefit of Ripretinib Dose Escalation After Disease Progression in Advanced Gastrointestinal Stromal Tumor: An Analysis of the INVICTUS Study

et al. 2021

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Background. Ripretinib 150 mg once daily (QD) is indicated for advanced gastrointestinal stromal tumor (GIST) as ≥fourth-line therapy. In INVICTUS, ripretinib intra-patient dose escalation (IPDE) to 150 mg twice daily (BID) was allowed after progressive disease (PD) on 150 mg QD by blinded independent central review using modified RECIST 1.1. We report the efficacy and safety of ripretinib IPDE to 150 mg BID after PD among patients randomized to ripretinib 150 mg QD in the INVICTUS study. Materials and Methods. Tumor imaging was performed every 28-day cycle for the first 4 cycles in the ripretinib 150 mg QD period and then every other cycle, including the 150 mg BID period. Among the ripretinib IPDE patients, progression-free survival (PFS)1 was the time from randomization until PD; PFS2 was the time from the first dose of ripretinib 150 mg BID to PD or death.Results. Among 43 ripretinib IPDE patients, median PFS1 was 4.6 months (95% confidence interval [CI], 2.7-6.4) and median PFS2 was 3.7 months (95% CI, 3.1-5.3). Median overall survival was 18.4 months (95% CI, 14.5-not estimable). Ripretinib 150 mg BID (median duration of treatment 3.7 months) was well tolerated with new or worsening Grade 3-4 TEAEs of anemia in 6 (14%) and abdominal pain in 3 (7%) patients. Ripretinib 150 mg BID was discontinued due to TEAEs in 7 (16%) patients. Conclusion. Ripretinib 150 mg BID after PD on 150 mg QD may provide additional clinically meaningful benefit with an acceptable safety profile in patients with ≥fourth-line GIST.TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT03353753 (INVICTUS) The Oncologist 2021;9999:• • Implications for Practice: Of the 85 patients with advanced gastrointestinal stromal tumor having received ≥3 prior anticancer therapies randomized to ripretinib 150 mg once daily (QD) in the phase 3 INVICTUS study, 43 underwent ripretinib intrapatient dose escalation (IPDE) to 150 mg twice daily (BID) after progressive disease (PD). Median progression-free survival was 4.6 months before and 3.7 months after ripretinib IPDE. The safety profile of ripretinib 150 mg BID was acceptable.

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“…Several targeted therapies also play the role of multikinase inhibitors [ 37 ], such as sorafenib [ 40 , 62 , 63 , 64 ], avapritinib [ 65 , 66 , 67 ], ponatinib [ 68 ], whose effectiveness is confirmed in adult GIST treatment; however, there has been any cohort evidence in the literature of clinical effectiveness in the pediatric population. Sorafenib has been used with excellent efficacy in 2 patients with BRAF-mutated wildtype GIST resistant to imatinib, sunitinib and regorafenib and has proved ineffective in BRAF V600E mutated GIST [ 69 ].…”

Section: Perspectives In Pharmacological Management Of Pediatric Gist...mentioning

confidence: 99%

Latest Advances in the Management of Pediatric Gastrointestinal Stromal Tumors

Andrzejewska

Czarny

Derwich

2022

Cancers

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Gastrointestinal stromal tumor is the most common mesenchymal neoplasm of the gastrointestinal tract, usually found in elderly adults. It is infrequent among pediatric patients and usually differs biologically from adult-type diseases presenting mutations of KIT and PDGFR genes. In this population, more frequent is the wild-type GIST possessing SDH, TRK, RAS, NF1 mutations, among others. Both tumor types require individualized treatment with kinase inhibitors that are still being tested in the pediatric population due to the different neoplasm biology. We review the latest updates to the management of pediatric gastrointestinal tumors with a particular focus on the advances in molecular biology of the disease that enables the definition of possible resistance. Emerging treatment with kinase inhibitors that could serve as targeted therapy is discussed, especially with multikinase inhibitors of higher generation, the effectiveness of which has already been confirmed in the adult population.

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Avapritinib in Patients With Advanced Gastrointestinal Stromal Tumors Following at Least Three Prior Lines of Therapy

Cited by 35 publications

References 29 publications

Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial

Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial

Clinical Benefit of Ripretinib Dose Escalation After Disease Progression in Advanced Gastrointestinal Stromal Tumor: An Analysis of the INVICTUS Study

Latest Advances in the Management of Pediatric Gastrointestinal Stromal Tumors

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